Merkel cell carcinoma (MCC) is a highly aggressive form of skin cancer that typically affects older and/or immunosuppressed individuals. Although MCC is relatively rare, its incidence in the U.S. has increased dramatically in the past decade. Earlier this year, DNA from a previously-unidentified polyomavirus was found to be present in a substantial majority of MCC tumors. The result suggests the possibility that the virus may be an etiologic cause of MCC and perhaps other forms of cancer. The Tumor Virus Molecular Biology Section is primarily focused on the biology of the human papillomavirus (HPV) virion. We have developed a useful panel of tools and reagents for analyzing the assembly, structure and infectious entry biology of HPV virions. Since the virions of HPVs and polyomaviruses are structurally similar, we feel that the Section may be well situated to rapidly answer several important questions about Merkel cell carcinoma polyomavirus (MCPyV) biology. In the half year since MCPyV was discovered, we have developed cutting-edge systems for generating MCPyV virus-like particles (VLPs) in mammalian cells. It has also been possible to produce MCPyV-based VLPs capable of delivering reporter genes to cultured cells, likely via the natural MCPyV infectious entry pathway. To begin to address the epidemiological prevalence of MCPyV serum responses, we have set up an intramural-extramural collaboration involving our group and Drs. Patrick Moore and Yuan Chang, the University of Pittsburgh team that originally discovered MCPyV. Preliminary data from this collaboration suggest that MCC patients exhibit much stronger serological responses to MCPyV VLPs than normal volunteers. This suggests that an MCPyV seroassay might serve as a diagnostic marker for MCC. In the longer term, we wish to address the possibility that MCPyV, or other as yet undiscovered polyomaviruses, are involved in other types of human cancer. A key question in this area is which tissues or cell types MCPyV targets during natural infection. We intend to use the MCPyV reporter virions to address this question. We would also like to develop a panel of monoclonal antibodies targeting the MCPyV virion proteins and intend to use these antibodies to screen various tumor samples for the possible presence of MCPyV virions. Although the project could be considered high-risk, we feel that innovation in this area of research is needed in order to address the intriguing hypothesis that this new family of polyomaviruses are an important new class of human carcinogens.